Sunscreen compounds

ABSTRACT

The invention relates to sunscreen compounds of formula I ##STR1## wherein R 1  is selected from alkyl, alkenyl, alkynyl substituted alkyl, substituted alkenyl, phenyl, substituted phenyl, substituted benzyl, cycloalkyl, cycloalkenyl, substituted cycloalkyl, substituted cycloalkenyl; 
     R 2  is selected from hydrogen, alkyl and alkoxy; 
     R 3  is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, phenyl, benzoyl, substituted phenyl, substituted benzyl, substituted benzoyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, alkanyoyl, substituted alkanoyl, the group OROROR 9  wherein R is a bivalent hydrocarbon radical and R 9  is alkyl, alkenyl, phenyl benzyl, substituted phenyl, substituted benzyl; 
     R 4  is alkyl or alkoxy; 
     n is an integer from 0 to 4; and 
     R 5  and R 6  are independently selected from alkyl, alkoxy, alkanoyl, alkanoyl substituted by hydroxyl or alkoxycarbonyl.

This is a division of application Ser. No. 07/236,530, filed May 26,1988, now U.S. Pat. No. 5,100,496.

The invention relates to sunscreen compositions comprising ultra-violetradiation absorbing compounds to methods of preparing such compositions,and to UV-absorbing compounds of particular use in preparing suchcompositions.

Sunscreen compositions may be used to form a coating for protectingsubstrates from harmful effects of ultraviolet radiation such as insolar radiation. For example, sunscreen compositions are probably bestknown for use in the protection of skin against severe erythra edemawhich can be caused by exposure to sunlight.

Common commercially available UV-agents include, for example,para-aminobenzoic acid derivatives, benzotriazoles, benzophenones,methoxycinnamates and salicylates. It has been proposed, for example inU.K. Patent Application 2,120,549A and French Patent Application8301391, that certain specific classes of vinylagous amide compounds(enaminoketones) may also be used as UV-absorbing sunscreen agents.

We have observed that certain mycosporine amino acids which exist in theliving tissue of the Pacific staghorn coral Acropora formosa arefunctional UV-absorbing agents (λmax 310-332 nm) in corals inhabitingthe shallow-water, tropical coral reef environment. While thesenaturally occurring enaminoketone compounds appear to be potentiallyattractive as commercial UV-agents, their utility is questionablebecause of the difficulty of isolating them from their biological sourceand because of their lack of adequate chemical stability. We haveproposed that certain synthetic vinylagous amide analogues of thosenatural products can be prepared which preserves their characteristicUV-absorbing chromophore within a chemically more stable structure andwhich typically have UV-absorption maxima (λmax) in the wavelengthregion 288-340 nanometers (P.C.T. Patent Application PCT/AU85/00242).These synthetic analogues, however, proved to be chemically unstableduring prolonged period of formulation and storage.

We have now found that a select group of cyclic vinylogous amidecompounds which comprise a tetrahydropyridine moiety are particularlysuitable for use in sunscreen compositions.

Accordingly we provide a sunscreen composition comprising as aneffective component thereof at least one compound of formula I ##STR2##wherein: R¹ is selected from the group consisting of: C₁ to C₁₈ alkyl;C₁ to C₉ alkyl substituted with a substituent selected from the group ofhydroxy, amino, C₁ to C₉ alkoxy, C₂ to C₉ alkenyloxy, C₁ to C₉ alkanoyl,(C₁ to C₉ alkoxy)carbonyl, carbamoyl, (C₁ to C₆ alkyl)carbamoyl andphenyl; C₂ to C₁₈ alkenyl; C₂ to C₉ alkenyl substituted with asubstituent selected from the group consisting of hydroxy, amino, C₁ toC₉ alkoxy, C₂ to C₉ alkenyloxy, C₁ to C₉ alkanoyl, carbamoyl, (C₁ to C₆alkyl)carbamoyl, and phenyl; C₂ to C₁₈ alkynyl; phenyl; the groupsphenyl and benzyl said groups being substituted in the benzene ring witha substituent is selected from the group of C₁ to C₁₂ alkyl, C₁ to C₁₂alkoxy, C₁ to C₁₂ alkenyloxy, C₁ to C₁₂ alkylamino, N,N-di(C₁ to C₆alkyl)amino, (C₁ to C₁₂ alkoxy)carbonyl and C₁ to C₁₂ alkanoyl; C₅ to C₇cycloalkyl; C₅ to C₇ cycloalkenyl; the groups substituted C₅ to C₇cycloalkyl and substituted C₅ to C₇ cycloalkenyl wherein the substituentis selected from the group of hydroxy, amino, C₁ to C₉ alkyl, C₁ to C₉alkoxy, and C₁ to C₉ alkenyloxy; polymers of one or more of the monomersselected from ethylene glycol, propylene glycol, styrene and C₂ to C₄alkenes, and derivatives of said polymers; and wherein R¹ may optionallylink together with R² via a bridging group of formula --(R⁷ R⁸ C)_(m-)wherein m is 2 or 3 and R⁷ (which may be the same or different) and R⁸(which may be the same or different) are independently selected from thegroup of hydrogen and C₁ to C₆ alkyl;

R² is selected from the group consisting of hydrogen, C₁ to C₆ alkyl, C₁to C₆ alkoxy, and the group wherein R¹ and R² together form a bridginggroup of formula --(CH⁷ R⁸)_(m) -- wherein R⁷, R⁸ and m are ashereinbefore defined;

R³ is selected from the group consisting of: C₁ to C₁₈ alkyl; C₁ to C₉alkyl substituted with a substituent selected from the group of amino,C₁ to C₉ alkoxy, C₂ to C₉ alkenyloxy, C₁ to C₉ alkanoyl, (C₁ to C₉alkoxy)carbonyl, carbamoyl, (C₁ to C₆ alkyl)carbamoyl, and phenyl; C₂ toC₁₈ alkenyl; C₂ to C₉ alkenyl substituted with a substituent selectedfrom the group consisting of hydroxy, amino C₁ to C₉ alkoxy, C₂ to C₉alkenyloxy, C₁ to C₉ alkanoyl, (C₁ to C₉ alkoxy)carbonyl, carbamoyl, (C₁to C₉ alkyl)carbamoyl and phenyl; C₂ to C₁₈ alkynyl; phenyl; benzoyl;the groups phenyl, benzyl and benzoyl said group being substituted inthe benzene ring with a substituent selected from the group of hydroxy,amino, C₁ to C₁₂ alkyl, C₂ to C₁₂ alkenyl, C₁ to C₁₂ alkoxy, C₂ to C₁₂alkenyloxy, C₁ to C₁₂ alkylamino, N,N-di(C₁ to C₆ alkyl)amino, (C₁ toC₁₂ alkoxy)carbonyl, and C₁ to C₁₂ alkanoyl; C₅ to C₇ cycloalkyl; C₅ toC₇ cycloalkenyl; the groups substituted C₅ to C₇ cycloalkyl andsubstituted C₅ to C₇ cycloalkenyl wherein the substituent is selectedfrom the group of hydroxy, amino, C₁ to C₉ alkyl, C₁ to C₉ alkoxy, andC₁ to C₉ alkenyloxy; C₁ to C₁₈ alkanoyl; C₂ to C₉ alkanoyl substitutedwith a substituent selected from the group of hydroxy, amino, C₁ to C₉alkoxy and C₂ to C₉ alkenyloxy, C₁ to C₉ alkanoyl; carbamoyl, (C₁ to C₆alkyl)carbamoyl, (C₁ to C₉ alkoxy)carbonyl and phenyl; polymers of oneor more monomers selected from ethylene glycol, propylene glycol,styrene and C₂ to C₄ alkenes, and derivatives of said polymers; and thegroup --OROROR⁹ wherein R (which may be the same or different) is abivalent hydrocarbon radical of 2 to 6 (more preferably 2 to 4) carbonatoms and R⁹ is a hydrocarbon radical selected from C₁ to C.sub. 6alkyl, C₂ to C₆ alkenyl, phenyl, benzyl, C₁ to C₆ alkyl phenyl and (C₁to C₆ alkyl)benzyl (more preferably R⁹ is selected from C₁ to C₄ alkyland C₂);

R⁴ is selected from the group consisting of C₁ to C₆ alkyl and C₁ to C₆alkoxy;

n is an integer selected from 0 to 4 inclusive; and

R⁵ and R⁶ which maybe the same or different are selected from hydrogen,C₁ to C₆ alkyl, C₁ to C₆ alkoxy, C₁ to C₁₀ alkanoyl, C₁ to C₁₀ alkanoylsubstituted by carboxyl or (C₁ to C₆ alkoxy)carbonyl and wherein R⁵ andR⁶ may form a spiro-carbocyclic ring by the bridging group of formula II##STR3## wherein q is 2 or 3 and R¹⁰ and R¹¹ may be the same ordifferent at each carbon unit of the bridge and are independentlyselected from hydrogen and C₁ to C₈ alkyl.

The composition of the present invention may be applied to a surface toreduce the exposure of the surface to ultra-violet radiation. Thecomposition may be formulated, for example, as a solid, liquid, gel oraerosol and may generally comprise a carrier (extending medium) whichadapts the agent for application to a surface.

In a further embodiment of the invention, there is provided a method ofpreparation of a sunscreen composition comprising mixing at least onecompound of formula I with a carrier suitably adapted to allowapplication of said compound to a surface. Examples of suitable carriersmay include oils for example, mineral oils, paraffin, squalene and octylpalmetate and oil/alcohol mixtures.

In a specific example, at least one compound of formula I is combinedwith a water-insoluble liquid such as a paraffin oil to give an oilphase which is combined with an aqueous phase to form an oil-in-wateremulsion in the presence of a suitable emulsifier.

The temperature at which the composition is formed is not critical andmay be selected in accordance with the nature of to the componentsthereof. The temperature is typically in the range 0° to 150° C.(preferably 0° to 80°) although higher or lower temperatures may be usedif desired.

Further components such as perfumes, colouring agents, antioxidants andoxygen scavengers may be used in the composition of the presentinvention.

Examples of oxygen scavengers include compounds which in the presence ofoxygen are oxidised more readily than the compound of formula I. Anexample of an oxygen scavenger is sodium thiosulphate.

The composition may comprise additives making the composition useful asa cosmetic or phamaceutical.

One or more compounds of formula I may be utilized in the composition ofthe present invention and generally the concentration of saidcompound(s) is in the range of 0.5 to 20% by weight of the totalcomposition. However higher or lower concentrations may be used ifdesired depending on the degree of screening required.

Preferably in the compound of formula I R¹ is selected from C₁ to C₁₈alkyl;

C₁ to C₉ alkyl substituted with a substitutent selected from the groupconsisting of, hydroxy, amino, C₁ to C₉ alkoxy; C₁ to C₉ alkanoyl and(C₁ to C₉ alkoxy)carbonyl; C₁ to C₁₈ alkenyl; cyclohexyl; phenyl;benzyl; the groups phenyl and benzyl said groups being substituted inthe benzene ring with a substituent selected form the group of C₁ to C₉alkyl, C₂ to C₉ alkenyl, C₁ to C₉ alkoxy, C₁ to C₉ alkylamino, N,N-di(C₁to C₆ alkyl)amino, C₁ to C₉ alkanoyl and (C₁ to C₉ alkoxy)carbonyl; andwherein R¹ may optionally link together with R² via a bridging group offormula --CH₂ (R⁷ R⁸ C)CH₂ -- wherein R⁷ and R⁸ are independentlyselected from hydrogen and C₁ to C₆ alkyl;

R³ is selected from C₁ to C₁₈ alkyl; C₁ to C₉ alkyl substituted with asubstituent selected form the group consisting of hydroxy, amino, C₁ toC₉ alkoxy and C₁ to C₉ alkanoyl; C₂ to C₁₈ alkenyl; cyclohexyl; phenyl;benzyl; benzoyl; the groups phenyl, benzyl and benzoyl said groups beingsubstituted in the benzene ring with a substituent selected from thegroup of C₁ to C₉ alkyl, C₂ to C₉ alkenyl, C₁ to C₉ alkoxy, C₁ to C₉alkylamino, N,N-di(C₁ to C₆ alkyl)amino, C₁ to C₉ alkanoyl and (C₁ to C₉alkoxy)carbonyl; C₁ to C₁₈ alkanoyl; and C₂ to C₉ alkanoyl substitutedwith phenyl;

R² is selected from hydrogen and C₁ to C₆ alkyl; and wherein R² may linktogether with R¹ to form a bridging group of formula --CH₂ (R⁷ R⁸ C)CH₂-- wherein R⁷ and R⁸ are independently selected from hydrogen and C₁ toC₆ alkyl;

R⁴ is C₁ to C₆ alkyl; and

n is from 0 to 4, and

R⁵ and R⁶ are independently selected from hydrogen; the group of formulaIII ##STR4## R¹⁰ and R¹¹ are independently selected from C₁ to C₄ alkyland hydrogen; and R¹² is selected from hydrogen and C₁ to C₆ alkyl andwherein R⁵ and R⁶ may form a spiro-carbocyclic ring by the bridginggroup of formula II (a) ##STR5## wherein R¹⁰ and R¹¹ are independentlyselected from hydrogen and C₁ to C₄ alkyl.

Preferably wherein one of R⁵ and R⁶ is the group of formula III then theother is hydrogen.

More preferred R¹ compositions of the invention comprise at least onecompound of formula I wherein:

R¹ is selected from the group consisting of C₁ to C₁₈ alkyl; C₁ to C₁₈alkenyl; phenyl; and benzyl;

R² is hydrogen or C₁ to C₄ alkyl; and wherein R¹ and R² may form acarbocyclic ring by the bridging group of formula

    --CH.sub.2 (CR.sup.7 R.sup.8)CH.sub.2 --

wherein R⁷ and R⁸ are independently selected from hydrogen and C₁ to C₄alkyl;

R³ is selected from C₂ to C₁₈ alkyl; C₁ to C₉ alkyl substituted with asubstituent selected from the group consisting of hydroxy and C₁ to C₉alkoxy; C₁ to C₁₈ alkenyl; benzoyl; benzyl; benzoyl substituted with asubstituent selected from C₁ to C₆ alkyl and C₁ to C₆ alkoxy; and C₁ toC₉ alkanoyl;

R⁴ is C₁ to C₄ alkyl

n is from 0 to 3

R⁵ and R⁶ are selected such that they comply with one of thepossibilities selected from the group consisting of (i) R⁵ and R⁶ areindependently selected from hydrogen and C₁ to C₄ alkyl; (ii) one of R⁵and R⁶ is hydrogen and the other is a group of formula III ##STR6##wherein R¹⁰, R¹¹ and R¹² are independently selected from the groupconsisting of hydrogen and C₁ to C₄ alkyl; and (iii) the group whereinR⁵ and R⁶ form a spiro carbocyclic ring by the group of formula IIa##STR7## wherein R¹⁰ and R¹¹ are independently selected from the groupconsisting of hydrogen and C₁ to C₄ alkyl.

In a particularly preferred group of compositions of the invention thecompound of formula I is selected such that

R¹ is selected from the group consisting of C₁ to C₁₈ alkyl; C₁ to C₁₈alkenyl; phenyl; and benzyl;

R² is hydrogen or C₁ to C₄ alkyl; and wherein R¹ and R² may form acarbocyclic ring by the bridging group of formula

    --CH.sub.2 (CR.sup.7 R.sup.8)CH.sub.2 --

wherein R⁷ and R⁸ are independently selected from hydrogen and C₁ to C₄alkyl;

R³ is selected from C₁ to C₁₈ alkyl;

C₂ to C₁₈ alkenyl; benzoyl; benzyl; benzoyl substituted with asubstituent selected from C₁ to C₆ alkyl and C₁ to C₆ alkoxy; and C₃ toC₉ alkanoyl;

R is C₁ to C₄ alkyl;

n is from 0 to 3; and

R⁵ and R⁶ are independently selected from hydrogen and C₁ to C₄ alkyl.

Many of the compounds for use in preparing of compositions of theinventions are novel compounds.

According to a further embodiment of the invention there is thereforeprovided a compound of formula I ##STR8## wherein: R¹ is selected fromthe group consisting of: C₁ to C₁₈ alkyl; C₁ to C₉ alkyl substitutedwith a substituent selected from the group of hydroxy, amino, C₁ to C₉alkoxy, C₂ to C₉ alkenyloxy, C₁ to C₉ alkanoyl, (C₁ to C₉alkoxy)carbonyl, carbamoyl, (C₁ to C₆ alkyl)carbamoyl and phenyl; C₂ toC₁₈ alkenyl; C₂ to C₉ alkenyl substituted with a substituent selectedfrom the group consisting of hydroxy, amino, C₁ to C₉ alkoxy, C₂ to C₉alkenyloxy, C₁ to C₉ alkanoyl, carbamoyl, (C₁ to C₆ alkyl)carbamoyl, andphenyl; C₂ to C₁₈ alkynyl; phenyl; the groups phenyl and benzyl saidgroups being substituted in the benzene ring with a substituent isselected from the group of C₁ to C₁₂ alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂alkenyloxy, C₁ to C₁₂ alkylamino, N,N-di(C₁ to C₆ alkyl)amino, (C₁ toC₁₂ alkoxy)carbonyl and C₁ to C₁₂ alkanoyl; C₅ to C₇ cycloalkyl; C₅ toC₇ cycloalkenyl; the groups substituted C₅ to C₇ cycloalkyl andsubstituted C₅ to C₇ cycloalkenyl wherein the substituent is selectedfrom the group of hydroxy, amino, C₁ to C₉ alkyl, C₁ to C₉ alkoxy, andC₁ to C₉ alkenyloxy; polymers of one or more of the monomers selectedfrom ethylene glycol, propylene glycol, styrene and C₂ to C₄ alkenes,and derivatives of said polymers; and wherein R¹ may optionally linktogether with R² to form a carbocyclic ring by the bridging group offormula --(R⁷ R⁸ C)m-- wherein m is 2 or 3 and R⁷ (which may be the sameor different) and R⁸ (which may be the same or different) areindependently selected from the group of hydrogen and C₁ to C₆ alkyl;

R³ is selected from the group consisting of: C₂ to C₁₈ alkyl; C₁ to C₉alkyl substituted with a substituent selected from the group of amino,C₁ to C₉ alkoxy, C₂ to C₉ alkenyloxy, C₁ to C₉ alkanoyl, (C₁ to C₉alkoxy)carbonyl, carbamoyl, (C₁ to C₆ alkyl)carbamoyl and phenyl; C₂ toC₁₈ alkenyl; C₂ to C₉ alkenyl substituted with a substituent selectedfrom the group consisting of hydroxy, amino C₁ to C₉ alkoxy, C₂ to C₉alkenyloxy, C₁ to C₉ alkanoyl, (C₁ to C₉ alkoxy)carbonyl, carbamoyl, (C₁to C₉ alkyl) carbamoyl and phenyl; C₂ to C₁₈ alkynyl; phenyl; benzoyl;the groups phenyl, benzyl and benzoyl said groups being substituted inthe benzene ring with a substituent selected from the group of hydroxy,amino, C₁ to C₁₂ alkyl, C₂ to C₁₂ alkenyl, C₁ to C₁₂ alkoxy, C₂ to C₁₂alkenyloxy, C₁ to C₁₂ alkylamino, N,N-di-(C₁ to C₆ alkyl)amino, (C₁ toC₁₂ alkoxy)carbonyl, and C₁ to C₁₂ alkanoyl; C₅ to C₇ cycloalkyl; C₅ toC₇ cycloalkenyl; the groups substituted C₅ to C₇ cycloalkyl andsubstituted C₅ to C₇ cycloalkenyl wherein the substituent is selectedfrom the group of hydroxy, amino, C₁ to C₉ alkyl, C₁ to C₉ alkoxy, andC₁ to C₉ alkenyloxy; C₁ to C₁₈ alkanoyl; C₁ to C₉ alkanoyl substitutedwith a substituent selected from the group of hydroxy, amino, C₁ to C₉alkoxy and C₂ to C₉ alkenyloxy, C₁ to C₉ alkanoyl; carbomoyl, C₁ to C₆alkyl)carbamoyl, (C₁ to C₉ alkoxy)carbonyl and phenyl; polymers of oneor more monomers selected from ethylene glycol, propylene glycol,styrene and C₂ to C₄ alkenes, and derivatives of said polymers; and thegroup --OROROR⁹ wherein R (which may be the same or different) is abivalent hydrocarbon radical of 2 to 6 (more preferably 2 to 4) carbonatoms and R⁹ is a hydrocarbon radical selected from C₁ to C₆ alkyl, C₂to C₆ alkenyl, phenyl, benzyl, (C₁ to C₆ alkyl) phenyl and (C₁ to C₆alkyl)benzyl (more preferably R⁹ is selected from C₁ to C₄ alkyl and C₂to C₄ alkenyl);

R² is selected from the group consisting of hydrogen, C₁ to C₆ alkyl,and the group wherein R¹ and R² together form a bridging group offormula --(CR⁷ R⁸)_(m) -- wherein R⁷, R⁸ and m are as hereinbeforedefined;

R⁴ is selected from the group consisting of C₁ to C₆ alkyl and C₁ to C₆alkoxy;

n is an integer selected from 0 to 4 inclusive; and

R⁵ and R⁶ which may be the same or different are selected from hydrogen,C₁ to C₆ alkyl, C₁ to C₆ alkoxy C₁ to C₁₀ alkanoyl, C₁ to C₁₀ alkanoylsubstituted by carboxyl or (C₁ to C₆ alkoxy)carbonyl and wherein R⁷ andR⁸ may form a spiro-carbocylic ring by the bridging group of formula II##STR9## wherein q is 2 or 3 and R¹⁰ and R¹¹ may be the same ordifferent at each carbon unit of the bridge and are independentlyselected from hydrogen and C₁ to C₈ alkyl; with the proviso that when R¹is methyl R³ is not selected from the group of benzyl, hydroxyethyl andmethoxymethyl.

Where reference is made herein to a group comprising an alkyl, alkenylor alkynyl moiety it will be understood that said moiety may be astraight or branched chain moiety, for example, the group C₁ to C₁₈alkyl includes straight and branched chain alkyl of 1 to 18 carbon atomsand the group C₁ to C₉ alkoxy includes groups wherein the alkyl portionof the alkoxy group is straight or branched chain of from 1 to 9 carbonatoms.

In compounds of formula I, as hereinbefore described the substituents R¹and/or R³ may be a polymer of one or more of the monomers selected fromethylene glycol, propylene glycol and C₂ to C₄ alkenes and derivativesthereof. Examples of the derivatives may include derivatives comprisingat least one group of formula X1 (a) or X1 (b) ##STR10## wherein R¹, R²,R³, R⁴, R⁵, R⁶ and n are as hereinbefore defined. When the polymer is apolymer of ethylene glycol or propylene glycol examples of derivativesthereof may include ethers formed by a bond of the terminal oxygen witha radical selected from the group of C₁ to C₆ alkyl, phenyl, benzyl, andthe groups phenyl and benzyl substituted in the benzene ring with C₁ toC₉ alkyl. Preferably the polymers contain in the range of from 3 to 18monomeric units.

Preferably in the compounds of the invention of formula I R¹ is selectedfrom C₁ to C₁₈ alkyl; C₂ to C₉ alkyl substituted with a substituentselected from the group consisting of hydroxy, amino, C₁ to C₉ alkoxy,C₁ to C₉ alkanoyl and (C₁ to C₉ alkoxy)carbonyl; C₁ to C₁₈ alkenyl;cyclohexyl; phenyl; benzyl; the groups phenyl and benzyl said groupsbeing substituted in the benzene ring with a substituent selected fromthe group of C₁ to C₉ alkyl, C₂ to C₉ alkenyl, C₁ to C₉ alkoxy, C₁ to C₉alkanoyl and (C₁ to C₉ alkoxy)carbonyl; and wherein R¹ may optionallylink together with R² by the a bridging group of formula --CH₂ (R⁷ R⁸C)CH₂ -- wherein R⁷ and R⁸ are independently selected from hydrogen andC₁ to C₆ alkyl;

R³ is selected from C₂ to C₁₈ alkyl; C₁ to C₉ alkyl substituted with asubstituent selected from the group consisting of hydroxy, amino, C₁ toC₉ alkoxy and C₁ to C₉ alkanoyl; C₂ to C₁₈ alkenyl; cyclohexyl; phenyl;benzyl; benzoyl; the groups phenyl, benzyl and benzoyl said groups beingsubstituted in the benzene ring with a substituent selected from thegroup of C₁ to C₉ alkyl, C₂ to C₉ alkenyl, C₁ to C₉ alkoxy, C₁ to C₉alkanoyl and (C₁ to C₉ alkoxy)carbonyl; C₃ to C₁₈ alkanoyl; and C₂ toC₁₈ alkanoyl substituted with phenyl;

R² is selected from hydrogen and C₁ to C₆ alkyl; and wherein R² may linktogether with R¹ to form a carbocyclic ring by the bridging group offormula --CH₂ (R⁷ R⁸ C)CH₂ -- wherein R⁷ and R⁸ are independentlyselected from hydrogen and C₁ to C₆ alkyl;

R⁴ is C₁ to C₆ alkyl;

n is from 0 to 4; and

R⁵ and R⁶ are independently selected from hydrogen; the group of formulaIII ##STR11## wherein R¹⁰, R¹¹ and R¹² are independently selected fromC₁ to C₄ alkyl and hydrogen; and wherein R⁵ and R⁶ may form aspiro-carbocyclic ring by the bridging group of formula II (a) ##STR12##wherein R¹⁰ and R¹¹ are independently selected from hydrogen and C₁ toC₄ alkyl.

Preferably wherein one of R⁵ and R⁶ is the group of formula III then theother is hydrogen.

More preferably in compounds of the invention:

R¹ is selected from C₁ to C₁₈ alkyl; C₁ to C₆ alkyl substituted with asubstituent selected from C₁ to C₆ alkanoyl and (C₁ to C₆alkoxy)carbonyl; C₁ to C₁₈ alkenyl; phenyl; and benzyl;

R² is selected from hydrogen and C₁ to C₄ alkyl and wherein R¹ and R²may form a carbocyclic ring by the bridging group of formula

    --CH.sub.2 (R.sup.7 R.sup.8 C)CH.sub.2 --

wherein R⁷ and R⁸ are independently selected from hydrogen and C₁ to C₄alkyl. R³ is selected from C₂ to C₁₈ alkyl; C₁ to C₉ alkyl substitutedwith a substituent selected from the group consisting of hydroxy and C₁to C₉ alkoxy; C₁ to C₁₈ alkenyl; benzoyl; benzyl; benzoyl substitutedwith a substituent selected from C₁ to C₆ alkyl and C₁ to C₆ alkoxy; andC₃ to C₉ alkanoyl;

R⁴ is C₁ to C₄ alkyl;

n is from 0 to 3; and

R⁵ and R⁶ are selected such that they comply with one of thepossibilities selected from the group consisting of (i) R⁵ and R⁶ areindependently selected from hydrogen and C₁ to C₄ alkyl; (ii) one of R⁵and R⁶ is hydrogen and the other is a group of formula III ##STR13##wherein R¹⁰, R¹¹ and R¹² are independently selected from hydrogen and C₁to C₄ alkyl; and (iii) the group wherein R⁵ and R⁶ form a spirocarbocyclic ring by the diradical group of formula IIa ##STR14## whereinR¹⁰ to R¹¹ are independently selected from hydrogen and C₁ to C₄ alkyl.

Even more preferably compound of the invention are compounds of formulaI wherein:

R¹ is C₁ to C₉ alkyl;

R² is selected from hydrogen and C₁ to C₄ alkyl; and wherein R¹ and R²may form a carbocyclic ring by the bridging group of formula

    --CH.sub.2 (CR.sup.8 R.sup.9)CH.sub.2 --

wherein R⁸ and R⁹ are methyl;

R³ is selected from C₂ to C₉ alkyl, C₂ to C₉ alkenyl; C₁ to C₉ alkylsubstituted with a substituent selected from hydroxy, phenyl and C₁ toC₆ alkoxy; benzoyl; benzoyl substituted with a substituent selected fromthe group consisting of C₁ to C₆ alkyl and C₁ to C₆ alkoxy, and C₁ to C₉alkanoyl;

R⁴ is selected from C₁ to C₄ alkyl;

n is from 0 to 3;

R⁵ and R⁶ are selected such that they comply with one of thepossibilities selected from the group consisting of (i) R⁵ and R⁶ areindependently selected from hydrogen and C₁ to C₄ alkyl; (ii) one of R⁵and R⁶ is hydrogen and the other is a group of formula III ##STR15##wherein R¹⁰ and R¹¹ are methyl and R¹² is hydrogen or C₁ to C₄ alkyl;and (iii) the group wherein R⁵ and R⁶ form a spiro carbocyclic ring bythe diradical group of formula II a ##STR16## wherein R¹⁰ and R¹¹ aremethyl. Preferably when one of R⁵ and R⁶ is not hydrogen or C₁ to C₄alkyl then n is zero.

In the most preferred compounds of the invention: R¹ is seleted from thegroup consisting of methyl, ethyl, propyl and 4-methylbutyl; R² ishydrogen or methyl; and wherein R¹ and R² may form a carbocyclic ring bythe bridging group of formula:

    --CH.sub.2 (CR.sup.7 R.sup.8)CH.sub.2 --

wherein R⁷ and R⁸ are methyl;

R³ is selected from the group consisting of: C₁ to C₉ alkyl such as

propyl, butyl, 1-methylethyl, 1-ethylpropyl, 2-methylbutyl,3-methylbutyl, hexyl, 2-ethylhexyl, 1-methylpentyl, 1,1-dimethylbutyl,octyl, 1-methylheptyl and 3-methyl-2-butenyl;

2-phenylethyl; benzoyl, 3-methoxybenzoyl;

4-butylbenzoyl; propanoyl; benzyl; and cyclohexyl;

R⁴ is methyl;

n is chosen from 0 to 3 and is conveniently zero.

R⁵ and R⁶ are selected such that they comply with one of thepossibilities selected from the group consisting of (i) R⁵ and R⁶ areindependently selected from hydrogen and methyl; (ii) one of R⁵ and R⁶is hydrogen and the other is a group of formula III ##STR17## whereinR¹⁰ and R¹¹ are methyl and R₁₂ is ethyl; and (iii) the group wherein R⁵and R⁶ form a spiro carbocyclic ring by the diradical group of formulaIIa. ##STR18## wherein R¹⁰ and R¹¹ are methyl.

One group of compounds of the invention which may be used in preparationof sunscreen compositions include compounds of formula Ia ##STR19##wherein

R³, R⁴, R⁵ and R⁶ are as hereinbefore defined in relation to compoundsof the invention, R¹³ is C₁ to C₄ alkyl and y is from 0 to 3.

Preferrred compounds of formula Ia include compounds of formula I (a)(i) ##STR20## wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸ and n are as hereinbeforedefined.

Included in the more preferred compounds of the invention of formula I##STR21## are compounds where R⁵ and R⁶ are independently selected fromhydrogen, C₁ to C₆ alkyl and C₁ to C₆ alkoxy, preferably from hydrogenand C₁ to C₆ alkyl; more preferably from hydrogen and C₁ to C₄ alkylsuch as methyl; and R¹, R², R³, R⁴ and n are as hereinbefore defined.

For example, such compound include compounds wherein

R¹ is selected from the group consisting of methyl, ethyl, propyl,3-methylbutyl;

R² is hydrogen;

R³ is selected from the group consisting of propyl, 1-methylethyl,butyl, 3-methylbutyl, 2-ethylhexyl and 3-methyl-2-butenyl;

n is O; and

R⁵ and R⁶ are hydrogen.

The compounds of formula I (a) (i) include such compounds wherein R⁵ andR⁶ are hydrogen and R³ is as hereinbefore defined and n is 0, that isthe compounds of formula I(a)(ii) ##STR22## wherein R⁷ and R⁸ are ashereinbefore defined.

When in the compounds of formula I(a)R⁵ and R⁶ comprise the groups offormula III or formula IIa it is preferred that R⁷ is identical with thegroup R¹⁰ and R⁸ is identical with the group R¹¹.

Specific examples of compounds embraced by the invention include.##STR23##

The compounds of formula I may be prepared by a variety of methods andin a further aspect of the invention there is provided methods for thepreparation of compounds of the invention of formula I.

The compounds may generally be derived via a suitable tetrahydropyridinecompound of formula IV or via a pyridine derivative of formula V(wherein A are independently selected from hydrogen and R⁴). ##STR24##

The preparation of the compound of formula I from the pyridinederivative of formula V may be carried out by reduction of the compoundof formula V for example using hydrogen in the presence of a catalyst(such as palladium on charcoal catalyst) to give a compound of theinvention of formula I(c). ##STR25##

The pyridine derivative of formula V may be prepared from the compoundof formula VII (wherein A are independently selected from hydrogen andR⁴) reaction thereof with the compound of formula VI (wherein L is aleaving group). ##STR26## The preparation of a compound of formula Ifrom the compound of formula IV may be carried out by

reacting the compound of formula IV, preferably in the presence of abase, with a compound of formula VI wherein L is a leaving group.

The compound of formula IV having the specific formula IVa may beprepared by reduction of the pyridine of formula VII, for example usinghydrogen in the presence of a catalyst such as palladium on charcoal.

Alternatively the compound of formula IV (having the specific formulaIVb) may be prepared by chemical reduction of the compound of formulaVIII ##STR27## wherein A which may be the same or different is chosenfrom hydrogen or R⁴ as hereinbefore defined. ##STR28## (A isindependently selected from hydrogen and R⁴).

In compound of formula VI the leaving group (L) may be chosen by thoseskilled in the art. Examples of leaving groups include chloride,bromide, iodide, sulfate, nitrate, methylsulfate, ethylsulfate,tetrafluoroborate, hexafluorophosphate, hexafluoroantiminate,methanesulfonate, fluorosulfonate, fluoromethanesulfonate andtrifluoromethanesulfonate.

An alternative method of preparation of the compound of formula IV mayinvolve reaction of the compound of formula XII with a compound offormula XIII in the presence of a base such as an amine to give thecompound of formula XIV and hydrogenation of the compound of formula XIVto give the compound of formula IV(c) which may be converted as hereinbefore described to a compound of the invention of formula I having thespecific formula I(b).

A preferred example of this alternative method is the reaction of thecompound of XIII with mesityl oxide to give the compound of formula IVwhich has the formula XV which may be utilised in providing compounds offormula I having a 4,4,6-trimethyl substitution in the tetrahydropyridine ring, for example, the compound methyl1-butyl-4,4,6-trimethyl-1,4,5,6-tetrahydro-3-pyridyl ketone. ##STR29##(A is independently selected from hydrogen and R⁴)

A similar scheme may be used for more direct preparation of the compoundof formula I by reaction of the compound of formula XII with a compoundof formula XVI followed by hydrogenation of the intermediate of formulaXVII to give a compound of the invention of formula I(b). ##STR30##

There is further provided a process for preparation of a compound offormula I (a)(iii) ##STR31## wherein R⁵ and R⁶ together from the spirocarbocyclic ring by the diradical group of formula III a ##STR32## orone of R⁵ and R⁶ is hydrogen and the other is the group of formula III##STR33## and R³, R¹⁰, R¹¹ and R¹² are as hereinbefore defined; whichprocess comprises reacting a compound of formula IX with formaldehyde##STR34## in presence of an acid to give a compound of the invention offormula I (a)(iii) wherein R⁵ and R⁶ from said spiro carbocyclic ring offormula IIa; and optionally reacting the spiro carbocyclic moiety with abase of formula X.

    MOR.sup.12

    X,

wherein M is an alkali metal cation, to provide a compound of theinvention of formula I (a) (iii).

                                      TABLE 1a                                    __________________________________________________________________________     ##STR35##                                                                    Compound                                                                      No.   R.sup.1     R.sup.2                                                                          R.sup.3        R.sup.4                                   __________________________________________________________________________     1    CH.sub.3    H  CH(CH.sub.3).sub.2                                                                           --                                         2    CH.sub.3    H  n-C.sub.3 H.sub.7                                                                            --                                         3    CH.sub.3    H  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                         --                                         4    CH.sub.3    H  CH.sub.2 CHC(CH.sub.3).sub.2                                                                 --                                         5    CH.sub.3    H  CH.sub.2 CH(C.sub.2 H.sub.5)CH.sub.2 (C.sub.2).sub.2                          CH.sub.3       --                                         6    CH.sub.3    H  C.sub.2 H.sub.4 C.sub.6 H.sub.5                                                              --                                         7    CH.sub.3    H  COC.sub.6 H.sub.5                                                                            --                                         9    CH.sub.3    CH.sub.3                                                                         CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                         --                                        10    C.sub.2 H.sub.5                                                                           H  n-C.sub.4 H.sub.9                                                                            --                                        11    C.sub. 2 H.sub.5                                                                          H  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                         --                                        12    n-C.sub.3 H.sub.7                                                                         H  n-C.sub.3 H.sub.7                                                                            --                                        13    n-C.sub.3 H.sub.7                                                                         H  n-C.sub.4 H.sub.9                                                                            --                                        14    n-C.sub.3 H.sub.7                                                                         H  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                         --                                        15    CH.sub.2 (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                              H  n-C.sub.3 H.sub.7                                                                            --                                        16    C.sub.6 H.sub.5                                                                           H  n-C.sub.3 H.sub.7                                                                            --                                        38                                                                                   ##STR36##  H  CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                         --                                        39    CH.sub.3    H  C.sub.4 H.sub.9                                                                              4,4,6-(CH.sub.3).sub.3                    __________________________________________________________________________

                  TABLE 1b                                                        ______________________________________                                         ##STR37##                                                                    Compound                                                                      No         R.sup.3           R.sup.5, R.sup.6                                 ______________________________________                                        17         n-C.sub.3 H.sub.7 H, H                                             18         CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                            H, H                                             19         CCO.sub.6 H.sub.5 H, H                                             20         COC.sub.6 H.sub.4 (3)OCH.sub.3                                                                  H, H                                             21         COC.sub.6 H.sub.4 (3)OCH.sub.3                                                                  H, H                                             22         COC.sub.6 H.sub.4 (4)-n-C.sub.4 H.sub.9                                                         H, H                                             23         n-C.sub.6 H.sub.14                                                                              a                                                25         b                 a                                                26         CH.sub.2 C.sub.6 H.sub.5                                                                        a                                                27         n-C.sub.8 H.sub.18                                                                              a                                                28         CH.sub.2 CH(CH.sub.3)CH.sub.2 CH.sub.3                                                          a                                                29         CH.sub.2 CH.sub.2 OH                                                                            a                                                30         CH.sub.2 CH(CH.sub.3)CH.sub.2 CH.sub.3                                                          a                                                31         CH(C.sub.2 H.sub.5)CH.sub.2 CH.sub.3                                                            a                                                32         CH.sub.2 CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5                                                     a                                                33         CH(CH.sub.3)CH.sub.2 (CH.sub.2).sub. 3 CH.sub.3                                                 a                                                34         CH(CH.sub.3)CH.sub.2 (CH.sub.2).sub.4 CH.sub.3                                                  a                                                35         C(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                    a                                                36         b                 H, C                                             ______________________________________                                         ##STR38##                                                                     ##STR39##                                                                     ##STR40##                                                                

In a further embodiment of the invention, there is provided a method ofscreening a surface from ultra-violet radiation, the method comprisingapplying to the surface a composition comprising a compound of formula Ias hereinbefore described.

The compositions of the present invention are particularly useful forprotection of human skin against harmful effects of sunlight. Human skinis well known to be sensitive to sunlight containing radiation ofwavelengths between about 270 nm and 400 nm.

The UV-B region of ultra violet radiation (290-320 nm) has long beenknown to cause damage to skin but more recently concern has beenexpressed over the effect of UV-A radiation (above 320 nm).

Compositions of the present invention may be prepared comprising one ormore compounds of formula I and may provide screening in the UV-Aregion, the UV-B region or in both of these regions.

Consequently, in one embodiment of the invention there is provided amethod of protecting skin from ultra-violet radiation, the methodcomprising applying to the surface of the skin a composition ashereinbefore described.

A specific example of a sunscreen formulation which may be used inpreparation of compositions of the present invention includes thefollowing

    ______________________________________                                        Sunscreen lotion composition                                                                             % w/w                                              ______________________________________                                        Methyl para-hydroxy benzoate                                                                             0.25                                               Propyl para-hydroxy benzoate                                                                             0.10                                               Cetyl/Stearyl 2-Ethylhexanoate                                                                           2.00                                               "CARBOMER" 491 thickener (cross linked acrylic                                                           0.45                                               acid polymer)                                                                 Phenyl trimethicone        1.00                                               Stearic Acid               3.00                                               Sodium Hydroxide           0.15                                               Phenoxyethanol             0.30                                               Isopropyl Isostearate      5.00                                               Antioxidant (BHA, BHT, ascorbates, tocopherols)                                                          0.08                                               Glyceryl Monostearate & PEG 100 Stearate                                                                 1.00                                               Fragrance                  0.10                                               Sunscreen Compound         6.00                                               Disodium EDTA              0.05                                               Treated water              80.52                                              ______________________________________                                         ("CARBOMER" is a trade mark)                                             

The invention is now illustrated by, but in no way limited to, thefollowing examples.

EXAMPLE 1 Methyl 1-(1-methylethyl)-1,4,5,6-tetrahydro-3-pyridyl ketone(1)

a) 3-acetyl-1,4,5,6-tetrahydropyridine was prepared by hydrogenation of3-acetyl pyridine in the presence of palladium on carbon according tothe method of Freifelder, J.Org.Chem. 29, 2895 (1964).

b) 3-acetyl-1,4,5,6-tetrahydropyridine (20.0 g, 0.16 mole) was addedunder nitrogen to a mixture of sodium hydride (5.76 g, 0.24 mole) anddry dimethylformamide (50 ml) stirring at 0° C. and stirring wascontinued for 15 minutes. 2-Bromopropane (21.5 g, 0.175 mole) was thenadded dropwise over 15 min, stirring continued for a further hour at 0°C. then overnight at room temperature. The reaction mixture wascautiously added to iced water (100 g) under nitrogen and extracted withdiethyl ether (3×100 ml). The combined organic phase was extracted withwater (150 ml), dried over magnesium sulphate, concentrated underreduced pressure to give methyl1-(1-methylethyl)-1,4,5,6-tetrahydro-3-pyridyl ketone (1). The productwas distilled as a pale yellow oil (b.pt 97°-98° C./0.5 mm Hg).

EXAMPLE 2 Methyl 1-propyl-1,4,5,6-tetrahydro-3-pyridyl ketone (2)

a) Methyl 1-propyl-1,4,5,6-tetrahydro-3-pyridyl ketone was prepared from3-acetyl-1,4,5,6-tetrahydropyridine and 1-bromopropane according to theprocedure of Part b) of Example 1. The product distilled as a paleyellow (b.pt 98°-100° C./0.5 mm Hg).

EXAMPLE 3 Methyl 1-(3-methylbutyl)-1,4,5,6-tetrahydro-3-pyridyl ketone(3)

Methyl 1-(3-methylbutyl)-1,4,5,6-tetrahydro-3-pyridyl ketone wasprepared from 3-acetyl-1,4,5,6-tetrahydropyridine and1-bromo-3-methylbutane according to the procedure of Part b) ofExample 1. The product distilled as a pale yellow oil (b.pt. 103°-106°C./0.1 mm Hg).

EXAMPLE 4 Methyl 1-(3-methyl-2-butenyl)-1,4,5,6-tetrahydro-3-pyridylketone (4)

a) A mixture of 3-acetylpyridine (12.1 g, 0.1 mole) and1-bromo-3-methyl-2-butene (22.3 g, 0.15 mole) was stirred at roomtemperature under nitrogen overnight. The mixture was diluted withdiethyl ether (25 ml) and the cream coloured crystalline solid,1-(3-methyl-2-butenyl)-3-acetyl pyridinium bromide, was filtered offunder nitrogen.

b) 1-(3-methyl-2-butenyl)-3-acetyl-pyridinium bromide (27.0 g, 0.1 mole)and triethylamine (10.1 g, 0.1 mole) in ethyl alcohol (50 ml) over 5%palladium on carbon (5 g) was hydrogenated at room temperature andpressure until two molar equivalents of hydrogen was taken up. Thecatalyst was removed by filtration and the filtrate concentrated atreduced pressure. The semi-solid residue was diluted with diethyl ether(75 ml), the solid removed by filtration and the filtrate concentratedunder reduced pressure to leave a pale oil which solidified on standing.Recrystallisation from ethanol/water gave the product, methyl1-(3-methylbutenyl)-1,4,5,6-tetrahydro-3-pyridyl ketone (4) as a paleyellow crystalline solid m.p. 76°-78° C.

EXAMPLE 5 Methyl 1-(2-ethylhexyl)-1,4,5,6-tetrahydro-3-pyridyl ketone(5)

a) 3-acetyl-1,4,5,6-tetrahydropyridine (20.0 g, 0.16 mole) was addedunder nitrogen to a mixture of sodium hydride (5.76 g, 0.24 mole) anddry tetrahydrofuran (50 ml) stirring at room temperature. After onehour, 1-bromo-2-ethyl hexane (33.8 g, 0.175 mole) was added dropwiseover 15 minutes and the mixture stirred overnight at room temperature.The reaction mixture was cautiously added to iced water (100 g) undernitrogen and extracted with diethyl ether (3×100 ml). The combinedorganic phase was dried over magnesium sulphate, concentrated underreduced pressure and the residue distilled to give methyl1-(2-ethylhexyl)-1,4,5,6-tetrahydro-3-pyridyl ketone (5) as a paleyellow oil (b.pt 140°-142° C./0.1 mm Hg).

EXAMPLE 6 Methyl 1-(2-phenylethyl)-1,4,5,6-tetrahydro-3-pyridyl ketone(6)

a) A mixture of 3-acetyl pyridine (12.1 g, 0.1 mole) and(2-bromoethyl)benzene (37.0 g, 0.2 mole) was heated at 100° C. undernitrogen for four hours. After cooling, the mixture was diluted withdiethyl ether (25 ml) and the pale brown crystalline solid, 1-(2-phenylethyl) -3-acetyl-pyridinium bromide, was filtered off under nitrogen.

b) A solution of 1-(2-phenylethyl)-3-acetylpyridinium bromide (30.6 g,0.1 mole) and triethylamine (10.1 g, 0.1 mole) in ethyl alcohol (50mole) over 5% palladium on carbon (5 g) was hydrogenated at roomtemperature and pressure. Upon cessation of hydrogen uptake, thecatalyst was filtered and the filtrate concentrated at reduced pressure.The semi-solid filtered and the filtrate concentrated under reducedpressure to leave a pale brown oil, methyl 1-(2-phenylethyl)-1,4,5,6-tetrahydro-3-pyridyl ketone (6).

EXAMPLE 7 Methyl 1-benzoyl-1,4,5,6-tetrahydro-3-pyridyl ketone (7)

a) Methyl 1-benzoyl-1,4,5,6-tetrahydro-3-pyridyl ketone was preparedfrom 3-acetyl-1,4,5,6-tetrahydropyridine and benzoyl chloride accordingto the procedure of Part b) of Example 1. The product was recrystallisedfrom ethanol/water m.pt. 93°-95° C.

EXAMPLE 8 AND EXAMPLE 9 Methyl1-(3-methylbutyl)-2-methyl-1,4,5,6-tetrahydro-3-pyridyl ketone (9)EXAMPLE 8

a) 4,4-Diacetylbutyronitrile was prepared by addition of acrylonitrileto the sodium salt of acetyl acetone according to the procedure ofJohnson et al, J.Chem.Soc (C), 1969, 176.

b) A solution of 4,4-diacetylbutyronitrile (15.3 g, 0.1 mole) in ethylalcohol (50 ml) over Raney nickel (2 g) was hydrogenated at roomtemperature and three atmospheres pressure. After hydrogen uptake hadceased, the catalyst was filtered off and the filtrate concentratedunder reduced pressure to give3-acetyl-2-methyl-1,4,5,6-tetrahydropyridine.

EXAMPLE 9 Methyl

1-(3-methylbutyl)-2-methyl-1,4,5,6-tetrahydro-3-pyridyl ketone wasprepared from 3-acetyl-2-methyl, 1,4,5,6-tetrahydro- pyridine and1-bromo-3-methylbutene according to the procedure of Part b) of Example1.

EXAMPLE 10 Ethyl 1-butyl-1,4,5,6-tetrahydro-3-pyridyl ketone (10)

a) A mixture of ethyl nicotinate (15.1 g, 0.1 mole), ethyl propionate(15.3 g, 0.15 mole) and sodium ethoxide (10.2 g, 0.15 mole) was stirredand heated under nitrogen at 100° C. for five hours. After cooling, themixture was diluted with water (150 ml) extracted with diethyl ether (50ml) and the aqueous layer made acidic to pH 1 with concentratedhydrochloric acid (50 ml). The aqueous layer was heated at 90° C. fortwo hours, cooled, made alkaline with solid potassium carbonate andextracted with diethyl ether (3×75 ml). The dried (magnesium sulphate)organic layer was concentrated and distilled to give ethyl 3-pyridylketone (b.pt 97°-99°/14 mm Hg).

b) Ethyl 3-pyridyl ketone was reacted with 1-bromobutane according tothe procedure of Para a) of Example 6 to give 1-butyl(3-pyridiniumbromide as a tan coloured crystalline solid.

c) 1-Butyl-3-propionyl pyridinium bromide was hydrogenated according tothe procedure described in Para b) at Example 6 to give ethyl1-butyl-1,4,5,6-tetrahydro-3-pyridyl ketone (10). The product wasdistilled as a pale yellow oil (b.pt. 108°-109° C./0.1 mm Hg).

EXAMPLE 11 Ethyl 1-(3-methylbutyl)-1,4,5,6-tetrahydro-3-pyridyl ketone(11)

a) Ethyl 3-pyridyl ketone was reacted with 1-bromo-3-methylbutaneaccording to the procedure of Parb a) of Example 6 to give1-(3-methylbutyl)-3-propionyl pyridinium bromide as a pale browncrystalline solid.

b) 1-(3-Methylbutyl)-3-propionyl pyridium bromide was hydrogenatedaccording to the procedure of Parb b) of Example 6 to give ethyl1-(-3-methylbutyl-1,4,5,6-tetrahydro-3-pyridyl ketone. The product wasdistilled as a pale yellow oil (b.pt. 111°-112° C./0.02 mm Hg).

EXAMPLE 12 Propyl 1-propyl-1,4,5,6-tetrahydro-3-pyridyl ketone (12)

a) A mixture of ethyl nicotinate (15.1 g, 0.1 mole), ethyl butyrate(17.4 g, 0.15 mole) and sodium ethoxide (10.2 g, 0.15 mole) was stirredand heated under nitrogen at 100° C. for five hours. After cooling, themixture was diluted with water (150 ml), extracted with diethyl ether(50 ml) and the aqueous layer made acidic to pH1 with concentratedhydrochloric acid (50 ml). The aqueous layer was heated at 90° C. for 2hours, cooled, and made alkaline with solid potassium carbonate andextracted with diethyl ether (3×75 ml). The dried (magnesium sulphate)organic layer was concentrated and distilled to give propyl 3-pyridylketone (b.pt. 118°-120° C./14 mm Hg).

b) Propyl 3-pyridyl ketone was reacted with 1-bromo-2-propene accordingto the procedure of Part a) of Example 4 to give1-(2-propenyl)-3-butyryl pyridium bromide as a cream colouredcrystalline solid.

c) 1-(2-Propenyl)-3-butyryl pyridinium bromide was hydrogenatedaccording to the procedure described in Part b) of Example 6 to givepropyl 1-propyl-1,4,5,6-tetrahydro-3-pyridyl ketone. The product wasdistilled as a pale yellow oil (b.pt 150°-153° C./0.3 mm Hg)

EXAMPLE 13 Propyl 1-butyl-1,4,5,6-tetrahydro-3-pyridyl ketone (13)

a) Propyl 3-pyridyl ketone was reacted with 1-bromobutane according tothe procedure of Part a) of Example 6 to give 1-butyl-3-butyrylpyridinium bromide as a tan coloured crystalline solid.

b) 1-Butyl-3-butyryl pyridinium bromide was hydrogenated according tothe procedure described in Part b) of Example 6 to give propyl1-butyl-1-4,5,6-tetrahydro-3-pyridyl ketone (13). The product wasdistilled as a pale yellow oil (b.pt. 120°-124° C./0.02 mm Hg).

EXAMPLE 14 Propyl 1-(3-methylbutyl)-1,4,5,6-tetrahydro-3-pyridyl ketone(14)

a) Propyl 3-pyridyl ketone was reacted with 1-chloro-3-methyl-2-buteneaccording to the procedure of Part a) of Example 4 to give1-(3-methyl-2-butenyl)-3-butyryl pyridinium chloride as a cream colouredcrystalline solid.

b) 1-(3-Methyl-2-butenyl)-3-butyryl pyridinium chloride was hydrogenatedaccording to the procedure described in Part b) of Example 6 to givepropyl 1-(3-methylbutyl)-1,4,5,6-tetrahydro-3-pyridyl ketone (14). Theproduct was distilled as a pale yellow oil (b.pt. 126°-129° C./0.02 mmHg).

EXAMPLE 15 4-Methylpentanyl 1-propyl-1,4,5,6-tetrahydro-3-pyridyl ketone(15)

a) A solution of 3-cyanopyridine (26.0 g, 0.25 mole) in dry diethylether (200 ml) was added dropwise over the hour to the Grignard reagentprepared from 1-bromo-3-methyl butane (40.7 g, 0.27 mole) and magensium(6.8 g, 0.26 mole) in dry diethyl ether (50 ml) under nitrogen. Themixture was heated at 35° C. for eight hours, cooled to roomtemperature, and diluted with cold saturated aqueous ammonium chloridesolution(200 ml) followed by concentrated hydrochloric acid (50 ml). Themixture was stirred for five hours, the ether layer separated, and theaqeuous layer boiled for two hours. The aqueous layer was neutralised topH9 with aqueous sodium hydroxide solution and extracted with diethylether (3×100 ml). The organic phase was dried (magnesium sulphate),concentrated under reduced pressure and distilled to give 3-methylbutyl3-pyridyl ketone.

b) 3-Methylbutyl 3-pyridyl ketone was reacted with 1-bromo-2-propeneaccording to the procedure of Part a) of Example 4 to give1-(2-propenyl)-3-(4-methyl)valeryl pyridinium bromide as a tan colouredcrystalline solid.

c) 1-(2-Propenyl)-3-(4-methyl)valeryl pyridinium bromide washydrogenated according to the procedure of Part b) of Example 6 to give4-methylpentanyl 1-propyl-1,4,5,6-tetrahydro-3-pyridyl ketone (15) as ayellow oil.

EXAMPLE 16 Phenyl 1-propyl-1,4,5,6-tetrahydro-3-pyridyl ketone (16)

a) 3-Benzoyl pyridine was reacted with 1-bromo-2-propene according tothe procedure of Part a) of Example 4 to give 1-(2-propenyl)-3-benzoylpyridinium bromide as a tan coloured crystalline solid.

b) 1-(2-Propenyl)-3-benzoyl pyridinium bromide was hydrogenatedaccording to the procedure of Part b) of Example 6 to give phenyl1-propyl-1,4,5,6-tetrahydro-3-pyridyl ketone (10) as a yellow oil.

EXAMPLE 177,7-Dimethyl-1,2,3,4,7,8-hexahydro-1-propyl-quinolin-5(6H)-one(17)

a) 7,7-Dimethyl-1,2,3,4,7,8-hexahydro-quinolin-5 (6H)-one [prepared bythe method of Grob and Kiefer, Helv. Chim Acta., 48 799, (1964)] wasreacted with 1-bromopropane according to the procedure of Part (b) ofExample 1 to give 7,7-dimethyl-1,2,3,4,7,8-hexahydro-1-propyl-quinolin-5(6H)-one (17) as an oil.

EXAMPLE 187,7-Dimethyl-1,2,3,4,7,8-hexahydro-1-(3-methylbutyl)-quinoline-5(6H)-one(18

a) 7,7-Dimethyl-1,2,3,4,7,8-hexahydro-quinolin-5(6H)-one was reactedwith 1-bromo-3-methylbutane according to the procedures of Part b) ofExample 1 to give7,7-dimethyl-1,2,3,4,7,8-hexahydro-1-(3-methylbutyl)-quinolin-5(6H)-one(18) as a pale yellow oil.

EXAMPLE 197,7-Dimethyl-1,2,3,4,7,8-hexahydro-1-benzoyl-quinolin-5(6H)-one(19)

a) 7,7 Dimethyl-1,2,3,4,7,8-hexahydro-quinolin-5(6H)-one was reactedwith benzoyl chloride according to the procedure of Part b) of Example 1to give7,7-dimethyl-1,2,3,4,7,8-hexahydro-1-benzoyl-quinolin-5(6H)-one(19) as ayellow solid.

EXAMPLE 207,7-Dimethyl-1,2,3,4,7,8-hexahydro-1-(3-methoxybenzoyl)-quinolin-5(6H)-one(20)

a) 7,7-Dimethyl-1,2,3,4,7,8-hexahydro-quinolin-5(6H)-one was reactedwith 3-methoxybenzoyl chloride according to the procedure of Part b) ofExample 1 to give7,7-dimethyl-1,2,3,4,7,8-hexahydro-1-(3-methoxybenzoyl)-quinolin-5(6H)-one(20) as a pale yellow solid.

EXAMPLE 217,7-Dimethyl-1,2,3,4,7,8-hexahydro-1-(4-methoxybenzoyl)-quinoline-5(6H)-one(21)

a) 7,7-Dimethyl-1,2,3,4,7,8-hexahydro-quinoline-5(6H)-one was reactedwith 4-methoxybenzoyl chloride according to the procedure of Part b) ofExample 1 to give7,7-dimethyl-1,2,3,4,7,8-hexahydro-1-(4-methoxybenzoyl)-quinoline-5(6H)-one(21)as a yellow waxy solid.

EXAMPLE 227,7-Dimethyl-1,2,3,4,7,8-hexahydro-1-(4-butylbenzoyl)-quinolin-5(6H)-one(22)

a) 7,7-Dimethyl-1,2,3,4,7,8-hexahydro-quinoline-5(6H)-one was reactedwith 4-butylbenzoyl chloride according to the procedure of Part b) ofExample 1 to give7,7-dimethyl-1,2,3,4,7,8-hexahydro-1-(4-butylbenzoyl)-quinoline-5(6H)-one(22)as a yellow solid.

EXAMPLE 23 Preparation of1,2,3,4,7,8-hexahydro-1-hexyl-4',4',7,7-tetramethylquinoline-3-spirocyclohexane-2',5(6H),c'-trione (23)

a) A solution of 5,5-dimethyl-3-hexylaminocyclohex-2-enone (26.76 g;0.12 mole), aqueous formaldehyde (37% w/w; 9 ml) and 2N hydrochloricacid (40 ml) was stirred at room temperature for 24h. The reaction waschilled on ice and made basic with 4N NH.OH. The resulting solid wascollected by filtration, washed with water (3×100 ml) and dried in vacuoto give 19.2 g (85.3%) of1,2,3,4,7,8-hexahydro-1-hexyl-4',4',7,7-tetramethylquinoline-3-spirocyclohexane-2',5(6H),6'-trione,m.p. 111.1°-113.0° C.

    max 314.0 mm (=27750)

EXAMPLE 24

The reaction solution of Example 23 consisting of5,5-dimethyl-3-hexylaminocyclohex-2-enone (26.76 g; 0.12 mole), aqueousformaldehyde (37% w/w; 9 ml) and 2N hydrochloric acid (40 ml) wasrefluxed for 5 h. The reaction mixture was chilled on ice, made basicwith 2NNH.OH, extracted into chloroform (3×100 ml) and dried over MgSO₄.Evaporation of the chloroform and crystallisation of the residue frombenzene/light petroleum gave 20.6 g (91.6%) of1,2,3,4,7,8-hexahydro-1-hexyl-4',4',7,7-tetramethylquinoline-3-spirocyclohexane-2',5(6H),6'-trione,m.p. 111.1°-113.0° C.

EXAMPLE 24

PMR (300 MHz; CDCl₃ ##STR41## C₂ (H₂) 3.438 (s;2H) C₃, (H₂) 2.140 (s;2H)C₄ (H₂) 2.883 (s;2H) C₄, (CH₃)₂ 1.318 (m;6H)

C₆ (H₂) 3.080 (s;1H) C₅, (H₂) 2.235 (m; 2H)

3.036 (s;1H)

C₇ (CH₃)₂ 0.916 (s;6H) C_(1"), (H₂) 3.331 (t;2H)

C₈ (H₂) 2.211 (s;1H) C_(2") -C_(4") (H₂)₃ 1.318 (m;6H)

2.258 (s;1H)

C_(5") (H₂) 1.690 (m;2H)

C_(6") (H₃) 0.894 (t;3H)

EXAMPLE 25-35 Preparation of1-substituted-1,2,3,4,7,8-hexahydro-4',4',7,7-tetramethylquinoline-3-spirocyclohexane-2',5(6H),6'-trionederivatives

The compound derivatives provided in Example 25-35 of the invention wereprepared by the general method described in Example 23 or Example 24 andare listed in Table I where the R³ -group is defined as the1-substituent.

                  TABLE 1                                                         ______________________________________                                        1-substituted (R.sup.3)-1,2,3,4,7,8-hexahydro-4',4',7,7-                      tetramethylquinoline-3-spirocyclohexane-2',5(6h),6'-                          trione derivatives                                                             ##STR42##                                                                    Ex-                                                                           am-                                                                           ple              λmax (mm)  M.P.                                       No.  R.sup.3     (MeOH)     ε(MeOH)                                                                      (°C.)                               ______________________________________                                        25   cyclohexyl  315.6      29230  203.1-204.5                                26   benzyl      313.0      28800  180.2-181.6                                27   n-octyl     314.4      28150  150-160/1Torr*                             28   2-methylbutyl                                                                             313.8      27100  115.7-116.9                                29   2-hydroxyethyl                                                                            317.0      27250  112.5-113.4                                30   2-ethylbutyl                                                                              315.6      27600  113.8-114.8                                31   3-pentyl    315.6      28260  119.0-120.0                                32   3-ethoxypropyl                                                                            315.4      27750  167.4-170.0                                33   3-heptyl    314.6      28410  211.0-212.9                                34   2-octyl     316.2      26300  160-180/1Torr*                             35   1,3-dimethyl-                                                                             315.2      24500  109.8-110.8                                     butyl                                                                    ______________________________________                                         *boiling point (°C./Torr).                                        

EXAMPLE 36 Preparation of ethyl3,3-dimethyl-5-(1,2,3,4,5,6,7,8-octahydro-1-cyclohexyl-7,7-dimethylquinolin-3-yl-5-oxopentanoate(36)

The compound of Example 36 was prepared by a reverse Dieckmann reactionby the general equation (R³ =cyclohexyl): ##STR43##

1,2,3,4,7,8-Hexahydro-1-cyclohexyl-4'4',7,7-tetramethylquinoline-3-spirocyclohexane-2',5(6H)6'-trione(Example 25; 6.6 g; 0.0175 mole) was added to ethanolic sodium hydroxide[from sodium (0.9 g)] and ethanol (80 ml)]. The mixture was refluxed for2h and the ethanol evaporated in vacuo. The residue was treated withice-cold water (100 ml) and the product extracted into chloroform (3×50ml). The chloroform layer was dried over MgSO₄ and evaporated to givethe crude ester (3.9 g; 54.0% as a pale yellow solid. The product wasrecrystalised from n-hexane/benzene to give pure ethyl3,3-dimethyl-5-(1,2,3,4,5,6,7,8-octahydro-1-cyclohexyl-7,7-dimethylquinoline-3-yl)-5-oxopentanoate,

m.p. 44°-46° C.

max 318.6 mm, =25,900

EXAMPLE 37

The compounds of Examples 1 to 24 inclusive were characterised by, andcan be identified by their 'H nuclear magnetic resonance spectra. The 'Hnuclear magnetic resonance spectra for the compounds of Examples 1 to 23are recorded in Table 2 below

                  TABLE 2                                                         ______________________________________                                        Com-                UV spectra                                                pound               λmax   'H N.M.R.                                   No.   Appearance    (nm)    log E δ in ppm (CDCl.sub.3)                 ______________________________________                                         1    pale yellow   312     4.47  1.20 s 3H                                         oil                         1.27 s 3h                                         bpt = 97-98°         1.63-1.94 q 2H                                    @ 0.5 mm Hg                 2.13 s 3H                                                                     2.22-2.47 q 2H                                                                3.01-3.20 t 2H                                                                3.33-3.68 Sept.1H                                                             7.40 s 1H                                    2    pale yellow   312     4.45  0.74-1.05 t 3H                                    oil                         1.38-1.96 m 4H                                    bpt = 98-100° C.     2.13 s 3H                                         @ 0.5 mm Hg                 2.18-2.49 m 2H                                                                2.91-3.29 m 4H                                                                7.32 s 1H                                    3    pale yellow   312     4.45  0.94 d 6H                                         oil                         1.40-1.60 m 3H                                    bpt = 103-106° C.    1.60-2.00 m 2H                                    @ 0.1 mm Hg                 2.10 s 3H                                                                     2.10-2.40 3H                                                                  2.10-2.40 q 2H                                                                3.00-3.30 q 4H                                                                7.30 s 1H                                    4    pale yellow   312     4.46  1.68 s 3H                                         solid                       1.76 s 3H                                         mpt = 76-78° C.      1.65-1.89 tt 2H                                                               2.12 s 3H                                                                     2.25-2.35 t 2H                                                                3.01-3.09 t 2H                                                                3.65-3.72 d 2H                                                                5.07-5.21 t 1H                                                                7.27 s 1H                                    5    pale yellow   311.8   4.53  0.75-1.03 t 6H                                    oil                         1.03-1.52 m 9H                                    bpt = 140-142° C.    1.52-1.96 m 2H                                    @ 0.1 mm Hg                 2.12 s 3H                                                                     2.19-2.44 t 2H                                                                2.95-3.20 t 4H                                                                7.26 s 1H                                    6    yellow oil    311.5   4.38  1.60-1.93 t 2H                                                                1.99 s 3H                                                                     2.09-2.39 m 2H                                                                2.72-2.97 t 2H                                                                3.00-3.24 t 2H                                                                3.27-3.54 t 2H                                                                7.02 s 1H                                                                     7.24 s 5H                                    7    yellow solid  289     4.27  1.74-2.03 m 2H                                    mpt = 93-95° C.      2.16 s 3H                                                                     2.27-2.51 t 2H                                                                3.64-3.88 t 2H                                                                7.50 s 5H                                                                     7.88 s 1H                                    9    pale yellow   318     4.45  0.90 s 3H                                         oil                         0.95 s 3H                                         bpt = 106-109° C.    1.31-1.98 m 5H                                    @ 0.1 mm Hg                 2.11 s 3H                                                                     2.22-2.51 m 2H                                                                2.41 s 3H                                                                     3.05-3.36 m 4H                              10    yellow oil    312     4.44  0.81-1.23 m 6H                                    bpt = 108-109° C.    1.23-1.99 m 6H                                    @ 0.1 mm Hg                 2.20-2.63 m 4H                                                                3.00-3.31 m4H                                                                 7.32 s 1H                                   11    pale yellow   312     4.42  0.90-0.96 d 6H                                    oil                         1.02-1.20 t 3H                                    bpt = 111-112° C.    1.20-1.62 m 3H                                    @ 0.02 mm Hg                1.62-1.94 tt 2H                                                               2.24-2.36 t 2H                                                                2.31-2.56 q 2H                                                                3.00-3.14 t 2H                                                                3.07-3.22 t 2H                                                                7.28 s 1H                                   12    pale yellow   313     4.49  0.90 t 6H                                         oil                         1.40-2.00 m 6H                                    bpt = 150-153° C.    2.20-2.50 m 4H                                    @ 0.3 mmHg                  3.00-3.20 m 4H                                                                7.30 s 1H                                   13    yellow oil    312     4.41  0.88-1.00 t 6H                                    bpt = 120-124° C.    1.08-1.95 m 8H                                    @ 0.02 mmHg                 2.27-2.45 m 4H                                                                3.03-3.20 m 4H                                                                7.25 s 1H                                   14    yellow oil    313     4.44  0.80-1.07 m 9H                                    bpt = 126-129°  C.   1.38-1.97 m 7H                                    @ 0.02 mm Hg                2.21-2.54 m 4H                                                                2.99-3.31 q 4H                                                                7.31 s 1H                                   15    yellow oil    308     4.21  0.74-1.08 t 9H                                                                1.34-1.99 m 7H                                                                2.42-2.61 m 4H                                                                2.88-3.29 m 4H                                                                7.30 s 1H                                   16    yellow oil    316     4.16  0.71-0.99 t 3H                                                                1.31-2.08 m 4H                                                                2.33-2.61 t 2H                                                                2.91-3.27 m 4H                                                                6.96 s 1H                                                                     7.37 s 5H                                   17    yellow oil    317.8   4.44  0.79-1.17 t 3H                                    bpt = 155-157° C.    1.15 s 6H                                         @ 0.1 mm Hg                 1.45-1.92 m 4H                                                                2.14 s 2H                                                                     2.26 s 2H                                                                     2.19-2.47 t 2H                                                                3.01-3.30 t 4H                              18    yellow oil    319     4.49  0.95 d 6H                                         bpt = 137-139°  C.   1.00 s 6H                                         @ 0.2 mmHg                  1.40-2.00 m 5H                                                                2.00-2.5 m 6H                                                                 3.1-3.3 m 4H                                19    yellow solid  302     4.22  1.04 s 6H                                         mpt = 113° C.        1.74-2.09 m 2H                                                                2.36 s 2H                                                                     2.74-2.60 m 4H                                                                3.70-3.91 t 2H                                                                7.67-8.02 m 4H                              20    pale yellow   300     4.44  1.00 s 6H                                         mpt = 112-114° C.    1.65-2.01 m 2H                                                                2.27-2.58 m 6H                                                                3.53-3.71 t 2H                                                                3.80 s 3H                                                                     6.96-7.33 m 4H                              21    yellow waxy   303     4.31  1.00 s 6H                                         solid                       1.64-2.04 m 2H                                                                2.27 s 2H                                                                     2.41 s 2H                                                                     3.48-3.78 m 2H                                                                3.87 s 3H                                                                     6.80-7.72 q 4H                              22    yellow solid  301.8   4.21  0.80-1.06 m 3H                                                                0.99 s 6H                                                                     1.06-2.08 m 8H                                                                2.27 s 2H                                                                     2.43 s 2H                                                                     2.58-2.76 t 2H                                                                3.56-3.77 t 2H                                                                7.19-7.59 q 4H                              ______________________________________                                    

EXAMPLE 38

1-[1-(3-methylbutyl)-1,4,5,6-tetrahydro-3-pyridyl]pentan-2,5-dione (38)

1-[1-(3-methylbutyl)-1,4,5,6-tetrahydro-3-pyridyl]pentan-2,5-dione canbe prepared from 1-(3-pyridyl)pentan-2,5-dione [obtained by the methodof Steller and Bchreckenburg Chem. Ber., 1078, 2453 (1974)] according tothe procedure of Example 14 parts (a) and (b).

EXAMPLE 39

Sunscreen compositions were prepared using the components shown in table2.

    ______________________________________                                        Part      Material         % w/w                                              ______________________________________                                        A         Water                69.5                                           B         Polypropylene glycol 20.0                                                     Meristyl Ether                                                                Glyceryl Stearate    5.0                                                      Oleth 10 surfactant  5.0                                                      Effective component  0.5                                                       BHT antioxidant                                                    C                              0.02/0.2                                                 Sodium thiosulphate                                                 ______________________________________                                    

Separate emulsion formulations were prepared using a mixture of parts Aand B for each of compounds No. 3, 5, 13 and 18 as the effectivecomponent and the pH was adjusted to 7 by dropwise addition of 1M NaOH.

Further compositions were prepared using a mixture of part A, B and Cfor each of compounds 3, 5, 13 and 18 as the effective component.

We claim:
 1. A compound of formula I ##STR44## wherein: R¹ is selectedfrom the group consisting of C₁ to C₁₈ alkyl; C₁ to C₉ alkyl substitutedwith a substituent selected from the group consisting of hydroxy, amino,C₁ to C₉ alkoxy, C₂ to C₉ alkenyloxy, C₁ to C₉ alkanoyl, (C₁ to C₉alkoxy) carbonyl, carbamoyl, (C₁ to C₆ alkyl)carbamoyl and phenyl; C₂ toC₁₈ alkenyl; C₂ to C₉ alkenyl substituted with a substituent selectedfrom the group consisting of hydroxy, amino, C₁ to C₉ alkoxy, C₂ to C₉alkenyloxy, C₁ to C₉ alkanoyl, carbamoyl, (C₁ to C₆ alkyl)carbamoyl, andphenyl; C₂ to C₁₈ alkynyl; phenyl; benzyl; the groups phenyl and benzylsubstituted on the benzene ring with a substituent selected from thegroup of C₁ to C₁₂ alkyl, C₁ to C₁₂ alkoxy, C₂ -C₉ alkylene, C₂ to C₁₂alkenyloxy, C₁ to C₁₂ alkylamino N,N-di(C₁ to C₆ alkyl)amino, (C₁ to C₁₂alkoxy)carbonyl and C₁ to C₁₂ alkanoyl; C₅ to C₇ cycloalkyl; C₅ to C₇cycloalkenyl; the groups substituted C₅ to C₇ cycloalkyl and substitutedC₅ to C₇ cycloalkenyl wherein the substituent is selected from the groupconsisting of hydroxy, amino, C₁ to C₉ alkyl, C₁ to C₉ alkoxy, and C₁ toC₉ alkenyloxy;R³ is selected from the group consisting of C₂ to C₁₈alkyl; C₁ to C₉ alkyl substituted with a substituent selected from thegroup consisting of hydroxy, amino, C₁ to C₉ alkoxy, C₂ to C₉alkenyloxy, C₁ to C₉ alkanoyl, (C₁ to C₉ alkoxy)carbonyl, carbamoyl, (C₁to C₆ alkyl)carbamoyl and phenyl; C₂ to C₁₈ alkenyl; C₂ to C₉ alkenylsubstituted with a substituent selected from the group consisting ofhydroxy, amino C₁ to C₉ alkoxy, C₂ to C₉ alkenyloxy, C₁ to C₉ alkanoyl,(C₁ to C₉ alkoxy)carbonyl, carbamoyl, (C₁ to C₉ alkyl) carbamoyl andphenyl; C₂ to C₁₈ alkynyl; phenyl; benzyl; benzoyl; the groups phenyl,benzyl and benzoyl optionally substituted on the benzene ring with asubstituent selected from the group consisting of hydroxy, amino, C₁ toC₁₂ alkyl, C₂ to C₁₂ alkenyl, C₁ to C₁₂ alkoxy, C₂ to C₁₂ alkenyloxy, C₁to C₁₂ alkylamino, N,N-di(C₁ to C₆ alkyl)amino, (C₁ to C₁₂alkoxy)carbonyl, and C₁ to C₁₂ alkanoyl; C₅ to C₇ cycloalkyl; C₅ to C₇cycloalkenyl; the groups substituted C₅ to C₇ cycloalkyl and substitutedC₅ to C₇ cycloalkenyl wherein the substituent is selected from the groupconsisting of hydroxy, amino, C₁ to C₉ alkyl, C₁ to C₉ alkoxy, and C₁ toC₉ alkenyloxy; C₁ to C₁₈ alkanoyl; C₂ to C₉ alkanoyl substituted with asubstituent selected from the group consisting of hydroxy, amino, C₁ toC₉ alkoxy, C₂ to C₉ alkenyloxy, C₁ to C₉ alkanoyl, carbamoyl, C₁ to C₆alkyl)carbamoyl, (C₁ to C₉ alkoxy)carbonyl and phenyl; and the group--OROROR⁹ wherein R which may be the same or different are bivalenthydrocarbon radicals of 2 to 6 carbon atoms and R⁹ is a hydrocarbonradical selected from C₁ to C₆ alkyl, C₂ to C₆ alkenyl phenyl, benzyl,(C₁ to C₆ alkyl) phenyl and (C₁ to C₆ alkyl)benzyl; R² is selected fromthe group consisting of hydrogen, C₁ to C₆ alkyl, C₁ to C₆ alkoxy; R⁴ isselected from the group consisting of C₁ to C₆ alkyl and C₁ to C₆alkoxy; n is an integer selected from 0 to 4 inclusive; R⁵ and R⁶ whichmay be the same or different are selected from hydrogen, C₁ to C₆ alkyl,C₁ to C₆ alkoxy, C₁ to C₁₀ alkanoyl, C₁ to C₁₀ alkanoyl substituted bycarboxyl or (C₁ to C₆ alkoxy) carbonyl;with the proviso that when R¹ ismethyl then R³ is not selected from the group of hydroxyethyl,methoxymethyl and benzyl and when R¹ is phenol, R³ is not acetyl oralkyl substituted with phenyl.
 2. A compound according to claim 1wherein: R¹ is selected from C₁ to C₁₈ alkyl; C₁ to C₉ alkyl substitutedwith a substituent selected from the group consisting of hydroxy, amino,C₁ to C₉ alkoxy, C₁ to C₉ alkanoyl and (C₁ to C₉ alkoxy)carbonyl; C₁ toC₁₈ alkenyl; cyclohexyl; phenyl; benzyl; the groups phenyl and benzylsaid groups being substituted in the benzene ring with a substituentselected from the group of C₁, to C₉ alkyl, C₂ to C₉ alkenyl, C₁ to C₉alkoxy, C₁ to C₉ alkanoyl and (C₁ to C₉ alkoxy) carbonyl;R³ is selectedfrom C₂ to C₁₈ alkyl; C₁ to C₉ alkyl substituted with a substituentselected from the group consisting of hydroxy, amino, C₁ to C₉ alkoxyand C₁ to C₉ alkanoyl; C₂ to C₁₈ alkenyl; cyclohexyl; phenyl; benzyl;benzoyl; the groups phenyl, benzyl and benzoyl said groups beingsubstituted on the benzene ring with a substituent selected from thegroup of C₁ to C₉ alkyl, C₂ to C₉ alkenyl, C₁ to C₉ alkoxy, C₁ to C₉alkanoyl and (C₁ to C₉ alkoxy)carbonyl; C₃ to C₁₈ alkanoyl; and C₂ to C₉alkanoyl substituted with phenyl; R² is hydrogen or C₁ or C₆ alkyl; R⁴is C₁ to C₆ alkyl; n is from 0 to 4; R⁵ and R⁶ are independentlyselected from hydrogen; C₁ to C₆ alkyl; the substituted alkanoyl groupof formula III ##STR45## wherein R¹⁰, R¹¹ and R¹² are independentlyselected from C₁ to C₄ alkyl and hydrogen.
 3. A compound according toclaim 2 wherein:R¹ is selected from the group consisting of C₁ to C₁₈alkyl; C₁ to C₆ alkyl substituted with a substituent selected from C₁ toC₆ alkanoyl and (C₁ to C₆ alkoxy) carboxyl; C₁ to C₁₈ alkenyl; phenyl,and benzyl; R² is hydrogen or C₁ to C₄ alkyl; R³ is selected from thegroup consisting of C₂ to C₁₈ alkyl; C₁ to C₉ alkyl substituted with asubstituent selected from the group consisting of hydroxy and C₁ to C₉alkoxy; C₁ to C₁₈ alkenyl; benzoyl; benzyl; benzoyl substituted with asubstituent selected from C₁ to C₆ alkyl and C₁ to C₆ alkoxy; and C₃ toC₉ alkanoyl; R⁴ is C₁ to C₄ alkyl; and n is an integer from 0 to 3; R⁵and R⁶ are selected from the group consisting of: (i) R⁵ and R⁶ areindependently selected from hydrogen and C₁ to C₄ alkyl and (ii) one ofR⁵ and R⁶ is hydrogen and the other is a group of formula III. ##STR46##wherein R¹⁰, R¹¹ and R¹² are independently selected from the groupconsisting of hydrogen and C₁ to C₄ alkyl.
 4. A compound according toclaim 3 wherein:R¹ is C₁ to C₉ alkyl; R² is selected from hydrogen andC₁ to C₄ alkyl; R³ is selected from C₂ to C₉ alkyl; C₂ to C₉ alkenyl; C₁to C₉ alkyl substituted with a substituent selected from hydroxy, phenyland C₁ to C₆ alkoxy; benzoyl; benzoyl substituted with a substituentselected from the group consisting of C₁ to C₆ alkyl and C₁ to C₆alkoxy; and C₃ to C₉ alkanoyl; R⁴ is C₁ to C₄ alkyl; n is from 0 to 3;R⁵ and R⁶ are consisting of(i) R⁵ and R⁶ are independently selected fromhydrogen and C₁ to C₄ alkyl; and (ii) one of R⁵ and R⁶ is hydrogen andthe other is a group of formula III ##STR47## wherein R¹⁰ and R¹¹ aremethyl and R¹² is hydrogen or C₁ to C₆ alkyl and wherein when one of R⁵and R⁶ is not hydrogen or C₁ to C₄ alkyl, then n is zero.
 5. A compoundaccording to claim 3 wherein:R¹ is C₁ to C₉ alkyl; R² is hydrogen; R³ isselected from the group consisting of C₁ to C₉ alkyl; 2-phenylethyl andcyclohexyl; R⁴ is methyln is chosen from 0 to 3; R⁵ and R⁶ are selectedfrom the group consisting of (i) R⁵ and R⁶ are independently selectedfrom hydrogen and methyl; and (ii) one of R⁵ and R⁶ is hydrogen and theother is a group of formula III ##STR48## wherein R¹⁰ and R¹¹ are methyland R¹² is ethyl; and wherein when at least one of R⁵ and R⁶ is nothydrogen or methyl, then n is zero.
 6. A compound of formula ##STR49##where R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, C₁ to C₆ alkyl and C₁ to C₆ alkoxy and R¹, R², R³, R⁴ and nare as defined according to claim
 1. 7. A compound according to claim 6wherein R⁵ and R⁶ are independently selected from hydrogen and C₁ to C₆alkyl.
 8. A compound according to claim 7 wherein R⁵ and R⁸ arehydrogen.
 9. A compound according to claim 3 wherein:R¹ is C₁ to C₁₈alkyl; R² is hydrogen; R³ is selected from the group consisting of C₂ toC₁₈ alkyl and C₂ to C₁₈ alkenyl; n is O; R⁵ and R⁶ are hydrogen.
 10. Acompound according to claim 6 wherein:R¹ is selected from the groupconsisting of methyl, ethyl, propyl, 3-methylbutyl; R² is hydrogen; R³is selected from the group consisting of propyl, 1-methylethyl, butyl,3-methylbutyl, 2-ethylhexyl, and 3-methyl-2-butenyl; n is 0; and R⁵ andR⁶ are hydrogen.
 11. A compound selected from the group consistingofmethyl 1-(3-methylbutyl)-1,4,5,6-tetrahydro-3-pyridyl ketone; methyl1-(3-methyl-2-butenyl)-1,4,5-6-tetrahydro-3-pyridyl ketone; ethyl1-butyl-1,4,5,6-tetrahydro-3-pyridyl ketone; ethyl1-(3-methylbutyl)-1,4,5,6-tetrahydro-3-pyridyl ketone; propyl1-propyl-1,4,5,6-tetrahydro-3-pyridyl ketone; propyl1-butyl-1,4,5,6-tetrahydro-3-pyridyl ketone;propyl-1-(3-methylbutyl)-1,4,5,6-tetrahydro-3-pyridyl ketone;4-methylpentyl 1-propyl-1,4,5,6-tetrahydro-3-pyridyl ketone; phenyl1-propyl-1,4,5,6-tetrahydro-3-pyridyl ketone; and methyl 1-butyl-4,4,6trimethyl-1,4,5,6-tetrahydro-3-pyridyl ketone.